Major difficulties in patients with epilepsy and brain tumors include refractory seizures, potential interactions between anticonvulsants and chemotherapeutic agents and enhanced risks of toxicity, including cognitive deterioration. For seizure control, levetiracetam, valproic acid, topiramate and lamotrigine can each be considered as agents of first choice. We advocate starting with levetiracetam monotherapy, based on efficacy, good tolerability and the absence of interactions. If levetiracetam alone is not sufficiently effective, we propose adding a second antiepileptic drug, rather than switching to monotherapy with another anticonvulsant. Under these circumstances we advise the use of valproic acid as an add-on over topiramate or lamotrigine, based on its reported clinical activity in brain tumor patients. The combination of levetiracetam and valproic acid seems synergistic, and produces few or no cognitive side effects. Antitumor therapy by neurosurgery, cranial radiation or chemotherapy contribute substantially to reducing seizure activity. Future research on seizure management in brain tumor patients should focus on better insight into the influence of multidrug resistance proteins on anticonvulsant drug transport over the blood-brain barrier, efficacy of new anticonvulsants with no or few interactions with other drugs, synergistic combinations of anticonvulsants in order to limit toxicity and therapeutic drug monitoring of anticonvulsants in current clinical practice and in new drug studies, including the effects of concomitant administration of chemotherapeutic agents.